Filoviruses, consisting of two major virus families including the ebolaviruses and marburgviruses (MARV and RAVV), cause periodic outbreaks of severe viral hemorrhagic fever with mortality rates as high as 90%. Since it is difficult to predict the species that would dominate future outbreaks, development of broadly protective therapeutics to prevent and manage future filovirus outbreaks is of high priority. In sharp contrast to the recent major breakthrough reported by us and others on isolation and development of a number of effective and broadly neutralizing mAbs (bNAbs) for ebolaviruses, only a single class of mAbs against marburgvirus GP has been described that target the same epitope within the receptor binding site (RBS) of MARV and RAVV GP. MR191 is the only MARV/RAVV GP RBS-specific monoclonal antibody (mAb) that has been shown to protect against MARV infection in nonhuman primates (NHPs) however at very high doses (2 doses of 50 mg/kg each). Thus, it is important to identify novel sites of vulnerability in MARV/RAVV GP and develop more potent immunotherapeutics against these deadly viruses. Having a variety of bNAbs will allow the design of therapeutic cocktails containing multiple mAbs targeting distinct epitopes, a strategy that has been shown tobe extremely effective against ebolaviruses to combat possible virus escape variants. There has been a long-standing and productive collaboration between Integrated BioTherapeutics (IBT) and University of Maryland (UMD) that has recently resulted in highly potent ebolavirus bNAbs with remarkable efficacy in animal models including nonhuman primate (NHP) and ferret models of EBOV, SUDV, and BDBV infection (Zhao et al., Cell 169, 891-904 e815 (2017)). Lately, using a prime/boost immunization strategy in NHPs combined with a novel memory B cell counter-screening with engineered GP mutants, we were able to isolate, for the first time, a group of highly potent MARV/RAVV bNAbs that target a new class of epitopes distinct from the RBS-binding MR series. In this STTR application, we aim to address the major challenge of MARV immunotherapy by developing top lead candidate marburgvirus therapeutic antibodies derived from these novel MARV/RAVV bNAbs. We will i) select 3-4 lead therapeutic mAbs among the current bNAb candidates; ii) optimize the lead mAbs and select for the final humanized/optimized candidate by state-of-the-art computer-aided optimization and efficacy study in a stringent guinea pig model of MARV infection; and iii) identify the final lead mAb (or cocktail) by testing the efficacy of candidates in NHP model of MARV infection. Upon completion of the proposed Phase I project we envision a Phase II project with the following objectives: i) expand the efficacy studies to RAVV and dose optimization in NHPs; ii) develop manufacturing cell lines in CHO cells, iii) develop bioanalytical methods for product release and PK, and iv) conduct safety and tissue cross reactivity studies using the GLP-grade clinical candidate. If successful, we anticipate further development of the product under DoD or BARDA funding and approval under FDA Animal Rule.